The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Bernhard Wunsch - One of the best experts on this subject based on the ideXlab platform.
-
Fluorinated GluN2B Receptor Antagonists with a 3-Benzazepine Scaffold Designed for PET Studies.
ChemMedChem, 2018Co-Authors: Marina Szermerski, Dirk Schepmann, Thomas Betzel, Ahmed Haider, Frederik Börgel, Simon M. Ametamey, Bernhard WunschAbstract:To analyze the N-methyl-d-aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B-subunit-containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1,7-diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7-position), 17 (9-position), 18a-c (1-position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18 F]14 was performed by nucleophilic substitution of the phenol 2 with 2-[18 F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18 F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981, and the non-labeled 3-Benzazepine 14 were able to abolish the specific binding of [18 F]14.
-
synthesis σ receptor affinity and pharmacological evaluation of 5 phenylsulfanyl and 5 benzyl substituted tetrahydro 2 Benzazepines
ChemMedChem, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Bernhard WunschAbstract:: In accordance with a novel strategy for generating the 2-Benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-Benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2-Benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-Benzazepine (19 b) and (±)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-Benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.
-
synthesis and pharmacological evaluation of like and unlike configured tetrahydro 2 Benzazepines with the α substituted benzyl moiety in the 5 position
Organic and Biomolecular Chemistry, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Kirstin Lehmkuhl, Roland Fröhlich, Bernhard WunschAbstract:A large set of tetrahydro-2-Benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-Benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the Benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-Benzazepines with various binding sites of the NMDA receptor were not observed.
-
heck reaction of ortho substituted iodobenzenes with α β unsaturated nitriles as a key step in the synthesis of tetrahydro 2 Benzazepines and hexahydro 3 benzazocines
Tetrahedron, 2013Co-Authors: Peer Hasebein, Dirk Schepmann, Katharina Aulinger, Bernhard WunschAbstract:Abstract A novel strategy is reported for the synthesis of tetrahydro-2-Benzazepines 2 and hexahydro-3-benzazocines 3 comprising a Heck reaction of ortho -substituted iodobenzenes 6 and 14 with α,β-unsaturated nitriles. Hydrogenation of the resulting α,β-unsaturated nitriles 7 , 11 , 15 , and 16 was followed by reductive cyclization. It was shown that the formation of 2-Benzazepines was faster than the formation of 3-benzazocines, which was explained by the higher stability of the aliphatic dimethyl acetals in 17 and 18 . The tetrahydro-2-Benzazepine 2d with an N -butyl residue reveals very high σ 1 affinity with a K i -value of 2.0 nM.
-
microwave assisted synthesis of 3 benzazepin 2 ones as building blocks for 2 3 disubstituted tetrahydro 3 Benzazepines
Tetrahedron, 2012Co-Authors: Soumya Sarkar, Dirk Schepmann, Syed Masood Husain, Roland Fröhlich, Bernhard WunschAbstract:Abstract Microwave assisted condensation of primary amines with keto acids 1a–c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH3 afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH3 reduction led to 3-Benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-Benzazepine (9c) reveals high σ1 affinity and selectivity over σ2 and NMDA receptors.
Dirk Schepmann - One of the best experts on this subject based on the ideXlab platform.
-
Fluorinated GluN2B Receptor Antagonists with a 3-Benzazepine Scaffold Designed for PET Studies.
ChemMedChem, 2018Co-Authors: Marina Szermerski, Dirk Schepmann, Thomas Betzel, Ahmed Haider, Frederik Börgel, Simon M. Ametamey, Bernhard WunschAbstract:To analyze the N-methyl-d-aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B-subunit-containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1,7-diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7-position), 17 (9-position), 18a-c (1-position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18 F]14 was performed by nucleophilic substitution of the phenol 2 with 2-[18 F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18 F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981, and the non-labeled 3-Benzazepine 14 were able to abolish the specific binding of [18 F]14.
-
Enantiomerically Pure 2‑Methyltetrahydro-3-benzazepin-1-ols Selectively Blocking GluN2B Subunit Containing N‑Methyl‑d‑aspartate Receptors
2015Co-Authors: Bastian Tewes, Bastian Frehland, Dirk Schepmann, Thomas Winckler, Dina Robaa, Tanaporn Uengwetwanit, Friedemann Gaube, Wolfgang Sippl, Bernhard WünschAbstract:A chiral pool synthesis was developed to obtain all four stereoisomeric 2-methyl-3-(4-phenylbutyl)tetrahydro-3-benzazepin-1-ols 21, 31, and 32 in a seven- to eight-step sequence. The phenols 32 reveal slightly higher GluN2B affinity than the methyl ethers 21. The GluN2B affinity increases in the order (1R,2S) < (1S,2S) < (1S,2R) < (1R,2R). The stereoisomeric phenols (R,R)-32 and (S,R)-32 show the highest GluN2B affinity and the highest cytoprotective activity. Both compounds represent GluN2B selective allosteric NMDA receptor antagonists. Docking of the 3-benzazepin-1-ols into the ifenprodil binding site of the crystallized GluN1b/GluN2B N-terminal domains led to free binding energies, which correlate nicely with the experimentally determined GluN2B affinities. The similar GluN2B affinity of the stereoisomeric phenols (S,S)-32, (R,R)-32, and (S,R)-32 is explained by different binding modes of the 3-Benzazepine scaffold. The benzyl ethers 31 reveal unexpectedly high GluN2B affinity but do not show cytoprotective effects. The additional benzyl moiety of 31 binds into a previously unrecognized lipophilic subpocket
-
synthesis σ receptor affinity and pharmacological evaluation of 5 phenylsulfanyl and 5 benzyl substituted tetrahydro 2 Benzazepines
ChemMedChem, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Bernhard WunschAbstract:: In accordance with a novel strategy for generating the 2-Benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-Benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2-Benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-Benzazepine (19 b) and (±)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-Benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.
-
synthesis and pharmacological evaluation of like and unlike configured tetrahydro 2 Benzazepines with the α substituted benzyl moiety in the 5 position
Organic and Biomolecular Chemistry, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Kirstin Lehmkuhl, Roland Fröhlich, Bernhard WunschAbstract:A large set of tetrahydro-2-Benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-Benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the Benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-Benzazepines with various binding sites of the NMDA receptor were not observed.
-
heck reaction of ortho substituted iodobenzenes with α β unsaturated nitriles as a key step in the synthesis of tetrahydro 2 Benzazepines and hexahydro 3 benzazocines
Tetrahedron, 2013Co-Authors: Peer Hasebein, Dirk Schepmann, Katharina Aulinger, Bernhard WunschAbstract:Abstract A novel strategy is reported for the synthesis of tetrahydro-2-Benzazepines 2 and hexahydro-3-benzazocines 3 comprising a Heck reaction of ortho -substituted iodobenzenes 6 and 14 with α,β-unsaturated nitriles. Hydrogenation of the resulting α,β-unsaturated nitriles 7 , 11 , 15 , and 16 was followed by reductive cyclization. It was shown that the formation of 2-Benzazepines was faster than the formation of 3-benzazocines, which was explained by the higher stability of the aliphatic dimethyl acetals in 17 and 18 . The tetrahydro-2-Benzazepine 2d with an N -butyl residue reveals very high σ 1 affinity with a K i -value of 2.0 nM.
Roland Fröhlich - One of the best experts on this subject based on the ideXlab platform.
-
synthesis and pharmacological evaluation of like and unlike configured tetrahydro 2 Benzazepines with the α substituted benzyl moiety in the 5 position
Organic and Biomolecular Chemistry, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Kirstin Lehmkuhl, Roland Fröhlich, Bernhard WunschAbstract:A large set of tetrahydro-2-Benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-Benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the Benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-Benzazepines with various binding sites of the NMDA receptor were not observed.
-
microwave assisted synthesis of 3 benzazepin 2 ones as building blocks for 2 3 disubstituted tetrahydro 3 Benzazepines
Tetrahedron, 2012Co-Authors: Soumya Sarkar, Dirk Schepmann, Syed Masood Husain, Roland Fröhlich, Bernhard WunschAbstract:Abstract Microwave assisted condensation of primary amines with keto acids 1a–c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH3 afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH3 reduction led to 3-Benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-Benzazepine (9c) reveals high σ1 affinity and selectivity over σ2 and NMDA receptors.
-
asymmetric synthesis of enantiomerically pure 2 substituted tetrahydro 3 Benzazepines and their affinity to σ1 receptors
Journal of Organic Chemistry, 2009Co-Authors: Syed Masood Husain, Dirk Schepmann, Roland Fröhlich, Bernhard WunschAbstract:A very short asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-Benzazepines is described. First, 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-ones 3a−d and 4a−d were synthesized by condensation of 2-(2-oxoalkyl)phenylacetic acids 1a−d with (R)-phenylglycinol (2). With the exception of the 11a-phenyl derivatives 3d/4d (ratio 91:9), the ratio of the diastereomeric 11a-alkyl derivatives 3a−c/ 4a−c was almost 50:50. The configuration of the newly formed chiral center in position 11a was proved by NOE experiments as well as X-ray crystal structure analysis. The reduction of the oxazolo[2,3-b][3]benzazepin-5(6H)-ones trans-3 and cis-4 with AlCl3/LiAlH4 (1:3) took place with retention of configuration and yielded 2,3-disubsituted tetrahydro-3-Benzazepines 10 and11. In the final step, removal of the N-(2-hydroxy-1-phenylethyl) residue from 10 and 11 by hydrogenolysis provided four pairs of enantiomerically pure 2-substituted tetrahydro-3-Benzazepines 12a−d and ent-12...
-
A very short asymmetric synthesis of enantiomerically pure methyl substituted tetrahydro-3-Benzazepines
Tetrahedron-asymmetry, 2008Co-Authors: S. Masood Husain, Roland Fröhlich, Bernhard WunschAbstract:Abstract An efficient synthesis of both enantiomers of methyltetrahydro-3-Benzazepines 10 and 15 has been elaborated following a very short reaction sequence. The two diastereomeric oxazolo[3]benzazepinones 6 and 7 were prepared by condensation of keto acid 4 with ( R )-phenylglycinol 5 . Benzylation of 6 and 7 was controlled by the newly established N/O-acetalic stereogenic center leading to products 11 and 12 . Reduction of the diastereomeric pairs 6 , 7 and 11 , 12 with LiAlH 4 /AlCl 3 (3:1) occurred under retention of configuration yielding tetrahydro-3-Benzazepines 8 and 9 with de >98%, as well as 13 and 14 with complete diastereoselectivity. Hydrogenolytic cleavage of the N-substituent led to the enantiomerically pure 2-methyltetrahydro-3-Benzazepines ( R )- 10 and ( S )- 10 and 1-benzyl-4-methyltetrahydro-3-Benzazepines ( R , R )- 15 and ( S , S )- 15 . The relative and absolute configuration of the formed products were deduced from X-ray crystal structure analysis of the 3-Benzazepine 14 ·HCl still bearing the original stereochemical information in the N-substituent.
Peer Hasebein - One of the best experts on this subject based on the ideXlab platform.
-
synthesis σ receptor affinity and pharmacological evaluation of 5 phenylsulfanyl and 5 benzyl substituted tetrahydro 2 Benzazepines
ChemMedChem, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Bernhard WunschAbstract:: In accordance with a novel strategy for generating the 2-Benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-Benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2-Benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-Benzazepine (19 b) and (±)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-Benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.
-
synthesis and pharmacological evaluation of like and unlike configured tetrahydro 2 Benzazepines with the α substituted benzyl moiety in the 5 position
Organic and Biomolecular Chemistry, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Kirstin Lehmkuhl, Roland Fröhlich, Bernhard WunschAbstract:A large set of tetrahydro-2-Benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-Benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the Benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-Benzazepines with various binding sites of the NMDA receptor were not observed.
-
heck reaction of ortho substituted iodobenzenes with α β unsaturated nitriles as a key step in the synthesis of tetrahydro 2 Benzazepines and hexahydro 3 benzazocines
Tetrahedron, 2013Co-Authors: Peer Hasebein, Dirk Schepmann, Katharina Aulinger, Bernhard WunschAbstract:Abstract A novel strategy is reported for the synthesis of tetrahydro-2-Benzazepines 2 and hexahydro-3-benzazocines 3 comprising a Heck reaction of ortho -substituted iodobenzenes 6 and 14 with α,β-unsaturated nitriles. Hydrogenation of the resulting α,β-unsaturated nitriles 7 , 11 , 15 , and 16 was followed by reductive cyclization. It was shown that the formation of 2-Benzazepines was faster than the formation of 3-benzazocines, which was explained by the higher stability of the aliphatic dimethyl acetals in 17 and 18 . The tetrahydro-2-Benzazepine 2d with an N -butyl residue reveals very high σ 1 affinity with a K i -value of 2.0 nM.
Olaf Krull - One of the best experts on this subject based on the ideXlab platform.
-
synthesis and structure nmda receptor affinity relationships of 1 substituted tetrahydro 3 Benzazepines
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Olaf Krull, Bernhard WunschAbstract:Abstract A novel synthesis of 1-substituted tetrahydro-1 H -3-Benzazepines 4 is described. Starting with (2-bromophenyl)acetaldehyde acetal 5 , the nitrostyrene 9 was prepared in three steps allowing the addition of various nucleophiles to yield the nitroacetals 10 . The one-pot Zn/HCl reductive cyclization of the nitroacetals 10 provided the 3-Benzazepines 4 , which were investigated for their affinity to the phencyclidine binding site of the NMDA receptor. A one-atomic spacer between the 3-Benzazepine system and the phenyl residue in position 1 seems to be favorable for high NMDA receptor binding. In this series the Benzazepine 4l substituted with the conformationally restricted and H-bond accepting acetanilide substituent in position 1 displays the highest NMDA receptor affinity ( K i =89 nM).
-
Synthesis and structure/NMDA receptor affinity relationships of 1-substituted tetrahydro-3-Benzazepines.
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Olaf Krull, Bernhard WunschAbstract:Abstract A novel synthesis of 1-substituted tetrahydro-1 H -3-Benzazepines 4 is described. Starting with (2-bromophenyl)acetaldehyde acetal 5 , the nitrostyrene 9 was prepared in three steps allowing the addition of various nucleophiles to yield the nitroacetals 10 . The one-pot Zn/HCl reductive cyclization of the nitroacetals 10 provided the 3-Benzazepines 4 , which were investigated for their affinity to the phencyclidine binding site of the NMDA receptor. A one-atomic spacer between the 3-Benzazepine system and the phenyl residue in position 1 seems to be favorable for high NMDA receptor binding. In this series the Benzazepine 4l substituted with the conformationally restricted and H-bond accepting acetanilide substituent in position 1 displays the highest NMDA receptor affinity ( K i =89 nM).